Топироксостат

Описание

Topiroxostat is an orally-administered, non-purine, selective xanthine oxidase (XO) inhibitor developed for the treatment of hyperuricemia specifically for patients with gout in Japan. The drug was discovered and developed by Fuji Yakuhin. In contrast to conventional XO inhibitors such as febuxostat, topiroxostat interacts with key amino acid residues of the solvent channel.

Химические свойства

Topiroxostat is soluble in organic solvents such as DMSO and dimethyl formamide (DMF). The solubility of topiroxostat in these solvents is approximately 10 and 20 mg/ml, respectively.

Использование

Topiroxostat is a selective xanthine oxidase inhibitor developed for treatment and management of hyperuricemia and gout. Xanthine oxidase, or xanthine oxidoreductase (XOR), regulates purine metabolism, and inhibition of the enzyme results in efficacious reduction of serum urate levels. Approved for therapeutic use in Japan since 2013, topiroxostat is marketed under the name Topiloric and Uriadec and is orally administered twice daily.

Биологическая активность

Topiroxostat is an inhibitor of xanthine oxidoreductase (IC50 = 5.3 nM), an enzyme that converts xanthine to urate. Formulations containing topiroxostat are effective in vivo, lowering urate levels in the serum of patients with hyperuricemia. In rats, but not primates, topiroxostat treatment results in the formation of xanthine crystals, resulting in nephritis. Topiroxostat also inhibits ATP-binding cassette transporter G2 (ABCG2; IC50 = 0.18 μM), a high-capacity urate transporter that functions in both renal and extrarenal urate secretion.

Фармаколо?гия

Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT‐1‐positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production. Abstract : Topiroxostat ameliorates proteinuria and renal injury independently of serum UA level in PAN‐induced nephrotic rats. Topiroxostat exerts a renoprotective effect owing to its antioxidant effects and property to lower UA levels in the kidney cortex.

Клиническое использование

Topiroxostat, a novel XO inhibitor, ameliorated proteinuria in association with podocyte injury markers such as decrease in WT-1 and podocin expressions and foot process effacement on electron microscope.